The rate of glucose metabolism by a living cell is known to be a useful indicator of a variety of abnormal physiological conditions, particularly in human patients. Included among these conditions are various forms of cancer, coronary artery disease, brain tumors and epilepsy. The diagnosis and locale determination of these conditions has been made possible by sophisticated imaging techniques that identify cells which are demonstrating abnormally high or low rates of glucose intake.
Until now, glucose imaging has been performed by positron-emission tomography (PET) with glucose analogs such as carbon-11-labeled glucose and 18F-labeled 2-deoxy-2-fluoro-D-glucose and its isomer 18F-labeled 3-deoxy-3-fluoro-D-glucose (collectively referred to as “FDG”). FDG, upon administration to the patient prior to the imaging procedure, enters the cell in the same manner as glucose. For instance, it is believed, without being bound to any particular theory, that FDG and glucose are transported through the cell membrane by glucose transporters Glut 1 and Glut 3. Both FDG and glucose are subsequently phosphorylated at the 6-position by hexokinase thereby forming D-glucose-6-phosphate and 2-deoxy-2-[18F]fluoro-D-glucose, respectfully. However, where D-glucose-6-phosphate is a substrate for the phosphohexose isomerase step in the metabolic pathway, 2-deoxy-2-[18F]fluoro-D-glucose does not complete the metabolic cycle inside the cells, and therefore accumulates and remains in the cells long enough for imaging to take place. The accumulation and the resulting whole body distribution of FDG as detected by the PET imaging procedure is an indicator of the stage and locus of the abnormality. PET is the imaging technique of choice because it is sensitive enough to usefully detect the annihilation photons emitted by FDG. Other imaging techniques, such as single-photon emission computed tomography (SPECT), do not have the sensitivity required to detect FDG.
Unfortunately, PET is one of the more costly imaging procedures. As a result, nuclear medicine scanning based on glucose transport abnormalities has enjoyed only limited use, and is feasible only at locations where PET equipment is available. This has hindered the development of glucose transport both as a research tool and as a diagnostic method.
As an alternative to FDG, it would be a significant advance in the art to develop a bioavailable glucose derivative that is labeled with a metal that is detectable by non-PET imaging methods.
Schibli, et al., disclose the preparation of glucose linked at the C-2, C-3, C-4 or C-6 sites with an ether (i.e., —O—) linkage to a complex consisting of 99mtechnetium or rhenium and a metal coordinating moiety selected from ethyleneiminodiacetic acid, propyleneiminodiacetic acid, octyleneiminodiacetic acid, ethylenepicolylamine mono acetic acid, ethylene histidyl and ethylenebisimidazolyl amino methane. No appreciable uptake of the glucose compounds was observed. See Schibli, et al., “Synthesis and in Vitro Characterization of Oraganometallic Rhenium and Technetium Glucose Complexes against Glut 1 and Hexokinase”, Bioconjugate Chem. 2005, 16, 105-112.
There is a need for glucose imaging compounds that exhibit cellular uptake, are not significantly metabolized in the cell, and that can be detected and quantified by imaging techniques other than PET.